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Updated: May 4, 2026
Evaluation of the Interplay Between the Complement Protein C1q and Hyaluronic Acid in Promoting Cell Adhesion
Published on: June 15, 2019
Plasma-derived mannose-binding lectin shows a direct interaction with C1-inhibitor
Mischa P Keizer1, Angela M Kamp2, Nannette Brouwer3
1Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, The Netherlands.
Abstract:
MBL-deficiency has been associated with an increased frequency and severity of infection, in particular in children and under immunocompromized conditions. In an open uncontrolled safety and pharmacokinetic MBL-substitution study using plasma-derived MBL (pdMBL) in MBL-deficient pediatric oncology patients, we found that despite MBL trough levels above 1.0μg/ml MBL functionality was not efficiently restored upon ex vivo testing. PdMBL showed C4-converting activity by itself, indicating the presence of MASPs. Upon incubation of pdMBL with MBL-deficient sera this C4-converting activity was significantly reduced. Depletion of the MASPs from pdMBL, paradoxically, restored the C4-converting activity. Subsequent depletion or inhibition of C1-inh, the major inhibitor of the lectin pathway, in the recipient serum restored the C4-converting activity as well. Complexes between MBL/MASPs and C1-inh (MMC-complexes) were detected after ex vivo substitution of MBL-deficient serum with pdMBL. These MMC-complexes could also be detected in the sera of the patients included in the MBL-substitution study shortly after pdMBL infusion. Altogether, we concluded that active MBL-MASP complexes in pdMBL directly interact with C1-inh in the recipient, leading to the formation of a multimolecular complex between C1-inh and MBL/MASPs, in contrast to the classical pathway where C1r and C1s are dissociated from C1q by C1-inh. Because of the presence of activated MASPs in the current pdMBL products efficient MBL-mediated host protection cannot be expected because of the neutralizing capacity by C1-inh.
Insights
Mannose-binding lectin (MBL) deficiency increases infection risk. Plasma-derived MBL (pdMBL) substitution therapy in deficient children did not restore MBL functionality due to C1-inhibitor (C1-inh) neutralizing MBL-associated serine proteases (MASPs).
Area of Science:
- Immunology
- Infectious Diseases
- Biochemistry
Background:
- Mannose-binding lectin (MBL) deficiency is linked to higher infection rates, particularly in vulnerable populations like pediatric cancer patients.
- MBL plays a crucial role in the innate immune system by initiating the lectin pathway of complement activation.
Purpose of the Study:
- To evaluate the safety and efficacy of plasma-derived MBL (pdMBL) substitution therapy in MBL-deficient pediatric oncology patients.
- To investigate the functional restoration of MBL activity in vivo and ex vivo following pdMBL administration.
Main Methods:
- An open, uncontrolled safety and pharmacokinetic study was conducted in MBL-deficient pediatric oncology patients receiving pdMBL.
- Ex vivo experiments involved testing pdMBL activity with MBL-deficient sera, assessing C4-converting activity, and analyzing the effects of MASP and C1-inhibitor (C1-inh) depletion or inhibition.
Main Results:
- Despite achieving target MBL trough levels, pdMBL did not efficiently restore MBL functionality in patients.
- PdMBL exhibited intrinsic C4-converting activity due to co-purified MASPs, which was reduced upon incubation with MBL-deficient sera.
- Depletion of MASPs from pdMBL or C1-inh from recipient serum restored C4-converting activity, indicating C1-inh neutralization of MBL-MASP complexes.
- Multimolecular complexes of C1-inh and MBL/MASPs (MMC-complexes) were detected post-infusion in patients, confirming in vivo interaction.
Conclusions:
- Plasma-derived MBL products contain active MBL-MASP complexes that are neutralized by C1-inh in the recipient.
- This interaction forms MMC-complexes, preventing efficient MBL-mediated complement activation and host protection.
- Current pdMBL products are unlikely to provide effective MBL-mediated immunity due to C1-inh neutralization of the incorporated MASPs.
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